Project Summary: The presence of HIV-1-specific immune responses in seronegative sex-workers and discordant partners indicates that it may be possible to induce an immune response that contains, clears, or protects from HIV-1 infection following repeated vaginal exposure. However, the mechanism of resistance to infection prior to generation of HIV-1 cell-mediated immune responses is not known. Of those examined, many of the women who remain seronegative, despite repeated heterosexual exposure to HIV-1, express HLA types uncommon to the surrounding population suggesting a role for alloimmune responses in their resistance to infection. As sexual activity frequently involves exposure to cellular material in secretions, mucosal surfaces may come in contact with MHC-mismatched alloantigens and MHC homologues (e.g. HIV-1 ENV) during sexual exposure. This is important as alloimmunization can elicit anti-HIV activity and reduce the susceptibility of cells to infection by HIV. Simian immunodeficiency virus (SIV) and feline immunodeficiency virus (FIV) cell-based vaccine studies provide additional evidence that alloantigen exposure may play a role in the protection against lentiviral infection. We hypothesize that there is a threshold for susceptibility to HIV-1 cervicovaginal infection that can modulated by repeated mucosal exposure to alloantigen. (We further hypothesize that alloantigen-induced responses may be particularly relevant for increasing the susceptibility threshold for infection by cell-associated virus). We will test this hypothesis using the FIV animal model, the only animal model of HIV-1 sexual transmission in which vaginal exposure to cell-associated virus, as well as cell-free virus, results in transmission, infection, and progression to immunodeficiency. We will determine whether repeated cervicovaginal exposure to alloantigen (1a) {induces allospecific soluble or cellular} immune responses, (1b) alters the in vitro susceptibility to infection and (2) alters the in vivo threshold for susceptibility to infection following vaginal challenge of cell-associated versus cell-free virus. Relevance: If we find that repeated cervicovaginal alloantigen exposure can reduce the susceptibility to infection, this would indicate that the threshold for vaginal infection can be modulated by direct vaginal exposure to non-viral antigen. Identification of the general mechanism by which alloantigen increases the threshold for infection will provide the basis for development and testing of topical therapies (e.g. mucosal adjuvants or topical microbicides) for the intervention of HIV-1 heterosexual transmission. Because these therapies would work in a virus non-specific manner, they would have potential use at the population level against multiple virus subtypes.